Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial
Menés respectivement sur 21 et 27 patients atteints d'un carcinome hépatocellulaire résécable, ces deux essais de phase II évaluent l'efficacité, du point de vue du taux de nécrose tumorale et du taux de réponse, et la toxicité de deux stratégies de traitement néoadjuvant, l'une à base de cémiplimab (un anti-PD-1) et l'autre à base de nivolumab, dispensé en monothérapie ou en combinaison avec l'ipilimumab
Background : Surgical resection of early stage hepatocellular carcinoma is standard clinical practice;however, most tumours recur despite surgery, and no perioperative intervention hasshown a survival benefit. Neoadjuvant immunotherapy has induced pathological responsesin multiple tumour types and might decrease the risk of postoperative recurrence inhepatocellular carcinoma. We aimed to evaluate the clinical activity of neoadjuvant cemiplimab (an anti-PD-1) in patients with resectable hepatocellular carcinoma.
Methods : For this single-arm, open-label, phase 2 trial, patients with resectable hepatocellularcarcinoma (stage Ib, II, and IIIb) were enrolled and received two cycles of neoadjuvantcemiplimab 350 mg intravenously every 3 weeks followed by surgical resection. Eligiblepatients were aged 18 years or older, had confirmed resectable hepatocellular carcinoma,an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate liverfunction. Patients were excluded if they had metastatic disease, if the surgery wasnot expected to be curative, if they had a known additional malignancy requiring activetreatment, or if they required systemic steroid treatment or any other immunosuppressivetherapy. After resection, patients received an additional eight cycles of cemiplimab350 mg intravenously every 3 weeks in the adjuvant setting. The primary endpoint was significant tumour necrosis on pathological examination (defined as >70% necrosis of the resected tumour). Secondary endpoints included delay of surgery, the proportion of patients with an overall response, change in CD8+ T-cell density, and adverse events. Tumour necrosis and response were analysed inall patients who received at least one dose of cemiplimab and completed surgical resection;safety and other endpoints were analysed in the intention-to-treat population. Patientsunderwent pre-treatment biopsies and blood collection throughout treatment. This trialis registered with ClinicalTrials.gov (NCT03916627, Cohort B) and is ongoing.
Findings : Between Aug 5, 2019, and Nov 25, 2020, 21 patients were enrolled. All patients receivedneoadjuvant cemiplimab, and 20 patients underwent successful resection. Of the 20patients with resected tumours, four (20%) had significant tumour necrosis. Three(15%) of 20 patients had a partial response, and all other patients maintained stabledisease. 20 (95%) patients had a treatment-emergent adverse event of any grade duringthe neoadjuvant treatment period. The most common adverse events of any grade wereincreased aspartate aminotransferase (in four patients), increased blood creatinephosphokinase (in three), constipation (in three), and fatigue (in three). Seven patientshad grade 3 adverse events, including increased blood creatine phosphokinase (in twopatients) and hypoalbuminaemia (in one). No grade 4 or 5 events were observed. Onepatient developed pneumonitis, which led to a delay in surgery by 2 weeks.
Interpretation : This report is, to our knowledge, the largest clinical trial of a neoadjuvant anti-PD-1monotherapy reported to date in hepatocellular carcinoma. The observed pathological responses to cemiplimab in this cohort support the design of larger trials to identifythe optimal treatment duration and definitively establish the clinical benefit ofpreoperative PD-1 blockade in patients with hepatocellular carcinoma.
The Lancet Gastroenterology & Hepatology , résumé, 2021